This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Males and females differ in their sensitivity to pain. Females generally have more pain complaints and are more sensitive to pain than males. We do not fully understand why these sex differences in pain perception exist. If we would understand this better, more effective therapies for pain complaints could be developed in the future. The aim of the present study is to assess what role sex hormones, such as estrogen and progesterone, play in changing sensitivity to pain. In this study we will look at the activity in the brain that is related to the processing of the painful or nonpainful stimuli by using functional Magnetic Resonance Imaging (fMRI), which is a noninvasive measurement of brain function. Also, we will examine if these hormones influence brain activity during a difficult distracting task and, thus, may be responsible for sex-differences in analgesic responses. We will examine normally cycling healthy females during a pre-fMRI screening and training session and 4 times during their normal menstrual cycle. In the pre-fMRI screening and training session, participants will be screened and they will fill out several questionnaires and undergo a training session of all procedures. This first session will be performed in the mid-follicular phase in all women. To make sure that each participant is in her mid-follicular phase, blood will be drawn and levels of estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and testosterone will be determined. Two different stimuli will be used to cause painful stimulation: pressure and electrical current stimulation will be given to the left dorsal foot. Both pressure and electrical current stimulation are commonly used in clinical situations. For each participant, 2 stimulus levels will be selected: a non-painful stimulus and a painful stimulus corresponding to a pain intensity rating of moderate intensity. Participants will have to rate their pain intensity and pain unpleasantness on a visual analogue scale after each stimulus. These scales will have anchors for 'no pain'/ 'not at all unpleasant', and 'most intense pain imaginable'/ 'extremely unpleasant'. After this first session, the subjects will be asked to keep a daily diary of their body temperatures and the onset and duration of their menstruation and ovulation with an ovulation test kit for at least two whole menstrual cycles. Candidates for further study participation will be selected on the basis of this first screening session and the menstrual cycle diaries. Then pain-related brain activation will be assessed in 4 different phases of the menstrual cycle since hormone levels will be different across these phases: during their menstrual phase (2-4 days after menstruation onset), their mid-follicular phase (6-8 days after menstruation onset), around ovulation (about 14 days after menstruation onset), and during midluteal phase (around 20 days after menstruation onset). On all of these visits, questionnaires will be filled out and sensory testing will be performed. In addition, subjects will participate in a functional brain imaging session in which cortical activity following stimulation with nonpainful and painful stimuli will be examined, and following presentation of a difficult mental task. At each visit, a sample of urine will be collected to test for pregnancy since there is currently not enough information about the effects of MRI scanning on an unborn child. At each test day, some blood will be drawn to measure levels of estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and testosterone. Levels of cortisol will be determined in saliva (spit) samples. The objective of the study is that 16 participants complete the study successfully. Since some of the participants may drop out during the study, we expect to recruit up to 32 participants in this study.